The goal of this project is to understand the cellular and molecular mechanisms governing bone growth and mineral metabolism. In the area of mineral metabolism, we recently demonstrated that activating mutations in the Ca2+-sensing receptor (CaR) gene cause autosomal dominant and sporadic hypoparathyroidism. To confirm that these mutations do, in fact, activate the CaR and to explore the mechanism of activation, the mutations were introduced into the human CaR cDNA and expressed in cultured cells. Some of the mutations caused a left-shift in the concentration-response curve, indicating an increase in sensitivity to calcium and suggesting an increase in affinity. Three of these mutations also showed an increase in maximal signal transduction capacity. This dual effect helps define the molecular mechanisms by which G-protein coupled receptors transduce signals across the cell membrane. In the area of bone growth, we have studied the effects of fibroblast growth factor (FGF)-2 in organ culture and in vivo. FGF-2 decreases growth plate chondrocyte proliferation, hypertrophy, and cartilage matrix production but stimulates angiogenesis and ossification of growth plate cartilage. These findings provide insight not only into the physiological role of FGFs in the growth plate, but also the pathophysiology of skeletal dysplasias caused by FGF receptor mutations. Ongoing work explores the role of retinoids in growth plate and the mechanisms determining spatial polarity in growth plate. Clinical studies are underway to determine the role of FGFR3 mutations in extreme short stature. Treatment trials using growth hormone or insulin-like growth factor-1 for the treatment of extreme short stature are also underway.